Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, of which treatment options are limited especially in advanced stage. Bufalin, the major digoxin-like component of the traditional Chinese medicine Chansu, exhibits significant antitumor activities in hepatoma cells, but the potential mechanism is obscure. Cell cycle-related kinase (CCRK) is recently identified to be a crucial oncogenic master regulator to drive hepatocarcinogenesis. Here we investigated the molecular function of bufalin on CCRK-regulated signaling pathway, and expounded the underlying mechanism in HCC suppression. In vitro with PLC5 HCC cells and human immortal LO2 cells, proliferation, malignant transformation and cell cycle progression assays were performed to evaluate the antitumor effect of bufalin. In vivo with xenograft and orthotopic mice models, tumor growths with weight and volume change were assessed with or without bufalin treatment. Western blot, RT-qPCR, immunofluorescence and immunohistochemistry were conducted to examine the expression level of CCRK and β-catenin/TCF signaling cascade. We revealed that bufalin suppresses PLC5 HCC cell proliferation, transformation and cell cycle progression rather than LO2 cells, which is correlated with CCRK-mediated β-catenin/TCF signaling. It was also confirmed in mice model. Thus, bufalin is a potential anti-HCC therapeutic candidate through the inhibition of CCRK-driven β-catenin/TCF oncogenic signaling pathway.
Highlights
Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, of which treatment options are limited especially in advanced stage
In HCC, we found that cycle-related kinase (CCRK) functions as an oncogenic master modulator to induce activation and nuclear translocation of β-catenin, where it forms a complex with nuclear transcription factor TCF
To explore the effect of bufalin on the growth of hepatic carcinoma cells, PLC5 HCC cells comparing with human immortalized LO2 hepatocytes were treated with bufalin at 7 different doses ranging from 0 to 1000 nmol/L
Summary
Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, of which treatment options are limited especially in advanced stage. We revealed that bufalin suppresses PLC5 HCC cell proliferation, transformation and cell cycle progression rather than LO2 cells, which is correlated with CCRK-mediated β-catenin/ TCF signaling. The multikinase inhibitor sorafenib improves clinical benefit of HCC treatment by targeting cell proliferation-related signaling pathways involved in genetic regulation and epigenetic modification[8,9], shedding light on the development of novel therapeutic strategies in HCC distinct from conventional therapeutic medicines. Further functional analysis confirmed that CCRK drives β-catenin/ TCF-dependent hepatocarcinogenesis via dysregulating cell cycle progression[23,24] These results consolidate that CCRK is a potential target for developing new therapeutic regimen against HCC
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